The mammalian nervous system includes a peripheral nervous system (PNS) and a central nervous system (CNS), including the brain and spinal cord, and is composed of two principal classes of cells, namely neurons and glial cells. The glial cells fill the spaces between neurons, nourishing them and modulating their function. During development, differentiating neurons from the central and peripheral nervous systems send out axons that grow and make contact with specific target cells. In some cases, axons must cover enormous distances with some growing into the periphery, whereas others are confined within the central nervous system. In mammals, this stage of neurogenesis is thought to be complete during the embryonic phase of life. Further, neuronal cells are generally thought not to multiply once they have fully differentiated.
A host of neuropathies, including neurodegenerative diseases, have been identified that affect the nervous system of mammals. These neuropathies, which may affect neurons themselves or associated glial cells, may result from cellular metabolic dysfunction, infection, injury, exposure to toxic agents, autoimmunity, malnutrition, and/or ischemia or may be due to age-related neurological changes. In some cases, the neuropathy is thought to induce cell death directly. In other cases, the neuropathy may induce sufficient tissue necrosis to stimulate the body's immune/inflammatory system and the immune response to the initial injury then destroys neural pathways. Also, neuronal tissue may be lost as a result of physical insult or trauma.
Loss of neurons, either directly or indirectly, was thought to be irreversible in the adult human brain, as it was long held that the generation of new neurons did not occur in the mature brain. In most brain regions, the generation of neurons is generally confined to a discrete developmental period. However, notable exceptions are found in the dentate gyrus and the subventricular zone of several species, where it has been shown that new neurons are generated well into the postnatal and adult period. Granule neurons are generated throughout life from a population of continuously dividing neural progenitor cells residing in the subgranular zone of the dentate gyms in the rodent brain.
“Newborn” neurons generated from these neural progenitor cells migrate into the granule cell layer, differentiate, extend axons and express neuronal marker proteins. The mechanisms and appropriate stimuli that promote the generation of new neurons, however, are largely unknown.
Attempts to counteract the effects of acute or neurodegenerative lesions of the brain and/or spinal cord have primarily involved implantation of embryonic neurons in an effort to compensate for lost or deficient neural or neurological function. However, human fetal cell transplantation research is severely restricted. Administration of neurotrophic factors, such as nerve growth factor and insulin-like growth factor, also has been suggested to stimulate neuronal growth within the CNS.
To date, however, no satisfactory agents or treatment methods exists to repair, or counteract, the neuronal damage associated with neuropathies, such as Parkinson's disease and Alzhemier's disease, neurological injury or neurological age-related decline or impairment. Accordingly, there is a need for new treatment modalities directed to improving the adverse neurological conditions associated with neuropathies, neurological injuries and age-related neurological decline or impairment.
Therefore, it is an object of the invention to provide compositions for the treatment or prevention of neuronal damage associated with neuropathies, such as Parkinson's disease and Alzheimer's disease, neurological injury or neurological age-related decline or impairment, and methods of making and using thereof.